Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer.

Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolised in the liver by cytochrome P450 mixed-function oxidase enzymes to isofosforamide mustard, the active alkylating compound. Mesna, a uroprotective thiol agent, is routinely administered concomitantly with ifosfamide, and has almost eliminated ifosfamide-induced haemorrhagic cystitis and has reduced nephron toxicity. Therapeutic studies, mostly noncomparative in nature, have demonstrated the efficacy of ifosfamide/mesna alone, or more commonly as a component of combination regimens, in a variety of cancers. In patients with relapsed or refractory disseminated nonseminomatous testicular cancer, a salvage regimen of ifosfamide/mesna, cisplatin and either etoposide or vinblastine produced complete response in approximately one-quarter of patients. As a component of both induction and salvage chemotherapeutic regimens, ifosfamide/mesna has produced favourable response rates in small cell lung cancer, paediatric solid tumours, non-Hodgkin's and Hodgkin's lymphoma, and ovarian cancer. Induction therapy with ifosfamide/mesna-containing chemotherapeutic regimens has been encouraging in non-small cell lung cancer, adult soft-tissue sarcomas, and as neoadjuvant therapy in advanced cervical cancer. As salvage therapy, ifosfamide/mesna-containing combinations have a palliative role in advanced breast cancer and advanced cervical cancer. Ifosfamide/mesna can elicit responses in patients refractory to numerous other antineoplastic drugs, including cyclophosphamide. With administration of concomitant mesna to protect against ifosfamide-induced urotoxicity, the principal dose-limiting toxicity of ifosfamide is myelosuppression; leucopenia is generally more severe than thrombocytopenia. Reversible CNS adverse effects ranging from mild somnolence and confusion to severe encephalopathy and coma can occur in approximately 10 to 20% of patients after intravenous infusion, and the incidence of neurotoxicity may be increased to 50% after oral administration because of differences in the preferential route of metabolism between the 2 routes of administration. Other adverse effects of ifosfamide include nephrotoxicity, alopecia, and nausea/vomiting. In general, intravenously administered mesna is associated with a low incidence of adverse effects; however, gastrointestinal disturbances are common following oral administration. Thus, ifosfamide/mesna is an important and worthwhile addition to the currently available range of chemotherapeutic agents. It has a broad spectrum of antineoplastic activity and causes less marked myelosuppression than many other cytotoxic agents. At present, the role of ifosfamide/mesna in refractory germ cell testicular cancer is clearly defined; however, its overall place in the treatment of other forms of cancer awaits delineation in future well-controlled comparative studies.     

Acrivastine. A review of its pharmacological properties and therapeutic efficacy in allergic rhinitis, urticaria and related disorders.

Acrivastine is a short acting histamine H1-receptor antagonist with a rapid onset of action. Double-blind clinical trials have shown acrivastine (usually 8mg three times daily) to be an effective and well tolerated antihistamine in the treatment of chronic urticaria and allergic rhinitis. Acrivastine was more effective than placebo and similar in efficacy to clemastine or terfenadine in the treatment of seasonal allergic rhinitis. In the treatment of dermatoses in which histamine has a pathogenetic role, the efficacy of acrivastine was superior to that of placebo and similar to that of usual dosages of clemastine, hydroxyzine, chlorpheniramine, cyproheptadine or terfenadine. Acrivastine caused less drowsiness than clemastine, the incidence of adverse effects being indistinguishable from that with placebo or terfenadine. Thus, acrivastine is an effective addition to drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Because of its rapid onset of action acrivastine will be particularly useful for 'on demand' therapy in patients with intermittent symptoms.     

Pasteurella haemolytica lipopolysaccharide-associated protein induces pulmonary inflammation after bronchoscopic deposition in calves and sheep.

The lipopolysaccharide (LPS)-associated protein (LAP) was extracted from Pasteurella haemolytica serotype A1 strains L101 (bovine origin) and 82-25 (ovine origin). Extracts contained 0.017% total LPS and appeared as only two bands at 14 and 16.6 kDa after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. To determine the extent of pulmonary inflammation induced by LAP and its possible role in the pathogenesis of pneumonic pasteurellosis, LAP (500 micrograms in pyrogen-free saline [PFS]) was deposited by fiber-optic bronchoscopy into the dorsum of the caudal portion of the cranial lobe of the right lung of calves (strain L101 LAP) and sheep (strain 82-25 LAP). LPS (500 micrograms in PFS), 3-h P. haemolytica cultures (1.6 x 10(8) to 1.9 x 10(8) CFU in PFS), and PFS alone were deposited similarly as controls. At necropsy, 24 h after deposition, gross and histologic pulmonary lesions of calves and sheep given LAP, LPS, and P. haemolytica were similar and consisted of various degrees of acute bronchopneumonia (relative severities of lesions induced: LAP < LPS < live organisms). By subjective histologic interpretation and semiquantitative morphometry, animals given LAP had the highest percentage of macrophages per alveolar lumen and the lowest percentage of neutrophils. The lesions from animals given LPS were more severe than those given LAP, but the morphometric cell counts were similar. In contrast, animals inoculated with P. haemolytica had lesions typical of this agent, consisting of many neutrophils, proteinaceous exudate, and a few macrophages. Morphometrically, these lesions had the highest numbers of neutrophils and the lowest numbers of macrophages. These studies show that LAP can induce an inflammatory response in the alveolar lumens and may play a role in the pathogenesis of pneumonic pasteurellosis.     

Timolol: a review of its therapeutic efficacy in the topical treatment of glaucoma.

Timolol maleate is a nonselective beta-blocking drug used for the topical treatment of increased intraocular pressure in patients with chronic open angle glaucoma. In comparative studies it has had a somewhat greater ocular hypotensive effect than the sympathomimetic agent adrenaline (epinephrine), or lower to medium concentrations (up to 4%) of the miotic drug pilocarpine, usually lowering intraocular pressure by about 30 to 35% (absolute pressure reduction). Timolol has been well tolerated by most patients, producing fewer subjective complaints than the comparison drugs, and objective measurements of ophthalmic status have not revealed any marked changes. Although some patients have been treated for extended periods without serious adverse effects or loss of effectiveness, further published reports in larger numbers of patients treated over several years are needed to confirm the drug's apparent long term safety and continued efficacy. Nevertheless, on the basis of present evidence, timolol appears to represent an important advance in the topical treatment of glaucoma.     

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.     

Piroxicam. A reappraisal of its pharmacology and therapeutic efficacy

Piroxicam is a chemically different non-steroidal anti-inflammatory drug with a long half-life which enables it to be administered once daily. This member of the oxicam series of compounds is now well established in the treatment of rheumatoid arthritis and osteoarthritis and has been shown to be a suitable alternative to aspirin, indomethacin, naproxen, ibuprofen, ketoprofen, sulindac, phenylbutazone and diclofenac in the treatment of rheumatic diseases. Open trials in many thousands of patients in hospital clinics and in general practice have demonstrated its analgesic and anti-inflammatory efficacy in a wide cross-section of patients with rheumatic diseases, when administered once daily either at night or in the morning, and recent studies have demonstrated its usefulness in musculoskeletal disorders, dysmenorrhoea and postoperative pain. Such studies have also demonstrated the generally good tolerability of piroxicam 20mg daily. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. The frequency and severity of these effects are dose related. Thus, piroxicam is now well established in the treatment of rheumatic diseases and offers an alternative to other analgesics in various pain states.